In the adult heart, cell death following myocardial infarction (MI) initiates an inflammatory reaction that removes dead cells and contributes to scar formation and cardiac repair. Since the regenerative capacity of the adult mammalian heart is limited, induction of this innate immune response could be maladaptive and compromises cardiac contractile function. In neonatal mice, the heart can regenerate fully without scarring following MI; however, this regenerative capacity is largely lost rapidly after birth. A proactive role of the immune system and its response to injury has been proposed to be a central mediator of neonatal heart regeneration. However, the exact mechanisms by which neonatal adaptive immunity modulates heart regeneration are largely unknown. We found that induction of MI in post-natal day 1 (P1) mice induced an inflammatory response that failed to activate key inflammatory serine proteases (ISPs), enzymes released upon leukocyte activation and are the primary reason for tissue damage at the sites of inflammation. In contrast, activation of ISPs was observed when MI was performed at P7 or later, a time when the regenerative capability of the heart is very low. Because activation of ISPs occurs early after myocardial injury, is an important regulator of the inflammatory response and functionally modulates a number of protein substrates that regulate cell growth and function, we hypothesize that activation of ISPs plays an active role in regulating cardiac regeneration and repair. Pilot study shows that inhibition of ISPs in vivo using mice deficient in DiPeptidyl Peptidase I (DPPI), a key enzyme necessary for the cleavage and activation of major ISPs, enhanced cardiomyocyte proliferation during post-natal development and in adult hearts subjected to MI compared to wild-type, along with an improvement in cardiac remodeling and function. Interestingly, DPPI deletion also enhanced the survival of stem cells in the infarcted area, suggesting that ISPs modulate post-MI repair by affecting not only cardiomyocyte growth and proliferation, but also by modulating stem cell survival and growth. These data support the hypothesis that activation of ISPs impairs endogenous cardiac repair and leads to cardiac dysfunction post-MI. Here, we will determine whether inhibition of ISPs enhances endogenous cardiac repair and regeneration in neonatal and adult heart after MI injury. We will also define the mechanisms by which ISPs modulate cardiac regeneration of neonatal and adult hearts. The long term goal is to develop novel strategies targeting DPPI to enhance cardiac repair after MI, for which not a single drug is currently available.